A mobile isocentric C-arm (Siemens PowerMobil) has been modified in our laboratory to include a large area flat-panel detector (in place of the x-ray image intensifier), providing multi-mode fluoroscopy and cone-beam computed tomography (CT) imaging capability. This platform represents a promising technology for minimally invasive, image-guided surgical procedures where precision in the placement of interventional tools with respect to bony and soft-tissue structures is critical. The image quality and performance in surgical guidance was investigated in pre-clinical evaluation in image-guided spinal surgery. The control, acquisition, and reconstruction system are described. The reproducibility of geometric calibration, essential to achieving high three-dimensional (3D) image quality, is tested over extended time scales (7 months) and across a broad range in C-arm angulation (up to 45 degrees), quantifying the effect of improper calibration on spatial resolution, soft-tissue visibility, and image artifacts. Phantom studies were performed to investigate the precision of 3D localization (viz., fiber optic probes within a vertebral body) and effect of lateral projection truncation (limited field of view) on soft-tissue detectability in image reconstructions. Pre-clinical investigation was undertaken in a specific spinal procedure (photodynamic therapy of spinal metastases) in five animal subjects (pigs). In each procedure, placement of fiber optic catheters in two vertebrae (L1 and L2) was guided by fluoroscopy and cone-beam CT. Experience across five procedures is reported, focusing on 3D image quality, the effects of respiratory motion, limited field of view, reconstruction filter, and imaging dose. Overall, the intraoperative cone-beam CT images were sufficient for guidance of needles and catheters with respect to bony anatomy and improved surgical performance and confidence through 3D visualization and verification of transpedicular trajectories and tool placement. Future investigation includes improvement in image quality, particularly regarding x-ray scatter, motion artifacts and field of view, and integration with optical tracking and navigation systems.

Background: Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. Methods:We randomised 2970 patients from 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were ≥45 years of age were eligible. Patients were randomly assigned to accelerated surgery (goal of surgery within 6 hours of diagnosis; 1487 patients) or standard care (1483 patients). The co-primary outcomes were 1.) mortality, and 2.) a composite of major complications (i.e., mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Outcome adjudicators were masked to treatment allocation, and patients were analysed according to the intention-to-treat principle; ClinicalTrials.gov, NCT02027896. Findings:The median time from hip fracture diagnosis to surgery was 6 hours (interquartile range [IQR] 4-9) in the accelerated-surgery group and 24 hours (IQR 10-42) in the standard-care group, p<0.0001. Death occurred in 140 patients (9%) assigned to accelerated surgery and 154 patients (10%) assigned to standard care; hazard ratio (HR) 0.91, 95% CI 0.72-1.14; absolute risk reduction (ARR) 1%, 95% CI -1-3%; p=0.40. The primary composite outcome occurred in 321 patients (22%) randomised to accelerated surgery and 331 patients (22%) randomised to standard care; HR 0.97, 95% CI 0.83-1.13; ARR 1%, 95% CI -2-3%; p=0.71.Interpretation: Among patients with a hip fracture, accelerated surgery did not significantly lower the risk of mortality or a composite of major complications compared to standard care.

1 Ruthenium(III) reacts with nitric oxide (NO) to form stable ruthenium(II) mononitrosyls. Several Ru(III) complexes were synthesized and a study made of their ability to bind NO, in vitro and also in several biological systems following expression of the inducible isoform of nitric oxide synthase (iNOS). Here we report on the properties of two, related polyaminocarboxylate-ruthenium complexes: potassium chloro[hydrogen(ethylenedinitrilo)tetraacetato]ruthenate (=JM1226; CAS no.14741-19-6) and aqua [hydrogen(ethylenedinitrilo)tetraacetato]ruthenium (=JM6245; CAS no.15282-93-6). 2 Binding of authentic NO by aqueous solutions of JM1226 yielded a product with an infrared (IR) spectrum characteristic of an Ru(II)-NO adduct. A compound with a similar IR spectrum was obtained after reacting JM1226 with S-nitroso-N-acetylpenicillamine (SNAP).3 The e ect of JM1226 or JM6245 on nitrite (NO 2 7 ) accumulation in cultures of macrophages (RAW 264 line) 18 h after stimulating cells with lipolysaccharide (LPS) and interferon-g (IFNg) was studied. Activation of RAW264 cells increased NO 2 7 levels in the growth medium from (mean+1 s.e.mean) 4.9+0.5 mM to 20.9+0.4 mM. This was blocked by actinomycin D (10 mM) or cycloheximide (5 mM). The addition of JM1226 or JM6245 (both 100 mM) to activated RAW264 cells reduced NO 2 7 levels to 7.6+0.2 mM and 8.8+0.6 mM, respectively. N G -methyl-L-arginine (L-NMMA; 250 mM) similarly reduced NO 2 7 levels, to 6.1+0.2 mM.4 The e ect of JM1226 or JM6245 on NO-mediated tumour cell killing by LPS+IFNg-activated macrophages (RAW 264) was studied in a co-culture system, using a non-adherent murine mastocytoma (P815) line as the`target' cell. Addition of JM1226 or JM6245 (both 100 mM) to the culture medium a orded some protection from macrophage-mediated cell killing: target cell viability increased from 54.5+3.3% to 93.2+7.1% and 80.0+4.6%, respectively (n=6). 5 Vasodilator responses of isolated, perfused, pre-contracted rat tail arteries elicited by bolus injections (10 ml) of SNAP were attenuated by the addition of JM1226 or JM6245 (10 74 M) to the perfusate: the ED 50 increased from 6.0 mM (Krebs only) to 1.8 mM (Krebs+JM6245) and from 7 mM (Krebs only) to 132 mM (Krebs+JM1226). Oxyhaemoglobin (5 mM) increased the ED 50 value for SNAP from 8 mM to 200 mM. 6 Male Wistar rats were injected with bacterial LPS (4 mg kg 71 ; i.p.) to induce endotoxaemia. JM1226 and JM6245 (both 100 mM) fully reversed the hyporesponsiveness to phenylephrine of tail arteries isolated from animals previously (24 h earlier) injected with LPS. Blood pressure recordings were made in conscious LPS-treated rats using a tail cu apparatus. A single injection of JM1226 (100 mg kg 71 , i.p.) administered 20 h after LPS (4 mg kg 71 , i.p.) reversed the hypotension associated with endotoxaemia. 7 The results show that JM1226 and JM6245 are able to scavenge NO in biological systems and suggest a role for these compounds in novel therapeutic strategies aimed at alleviating NO-mediated disease states.

The concept of metronomic photodynamic therapy (mPDT) is presented, in which both the photosensitizer and light are delivered continuously at low rates for extended periods of time to increase selective tumor cell kill through apoptosis. The focus of the present preclinical study is on mPDT treatment of malignant brain tumors, in which selectivity tumor cell killing versus damage to normal brain is critical. Previous studies have shown that low-dose PDT using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis in either tumor or normal brain tissue or apoptosis in the latter. On the basis of the levels of apoptosis achieved and model calculations of brain tumor growth rates, metronomic delivery or multiple PDT treatments, such as hyperfractionation, are likely required to produce enough tumor cell kill to be an effective therapy. In vitro studies confirm that ALA-mPDT induces a higher incidence of apoptotic (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate, sodium salt nick-end labeling positive) cells as compared with an acute, high-dose regimen (ALA-aPDT). In vivo, mPDT poses two substantial technical challenges: extended delivery of ALA and implantation of devices for extended light delivery while allowing unencumbered movement. In rat models, ALA administration via the drinking water has been accomplished at very high doses (up to 10 times therapeutic dose) for up to 10 days, and ex vivo spectrofluorimetry of tumor (9L gliosarcoma) and normal brain demonstrates a 3-4 fold increase in the tumor-to-brain ratio of PpIX concentration, without evidence of toxicity. After mPDT treatment, histological staining reveals extensive apoptosis within the tumor periphery and surrounding microinvading colonies that is not evident in normal brain or tumor before treatment. Prototype light sources and delivery devices were found to be practical, either using a laser diode or light-emitting diode (LED) coupled to an implanted optical fiber in the rat model or a directly implanted LED using a rabbit model. The combined delivery of both drug and light during an extended period, without compromising survival of the animals, is demonstrated. Preliminary evidence of selective apoptosis of tumor under these conditions is presented.